{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T12:02:38Z","timestamp":1793361758782,"version":"4.5.0"},"reference-count":26,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T00:00:00Z","timestamp":1639612800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81670919"],"award-info":[{"award-number":["81670919"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81970872"],"award-info":[{"award-number":["81970872"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81700900"],"award-info":[{"award-number":["81700900"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases","award":["14DZ2260300"],"award-info":[{"award-number":["14DZ2260300"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Elucidating the mechanism by which biallelic inactivation evolved could provide a mechanistic understanding for NF2 tumorigenesis and also a rationale for clinical management.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>A cohort of 60 NF2 patients was recruited. Next-generation sequencing of tumor and paired control samples was used to explore how NF2 mutations evolve in determining the clinical phenotypes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>In total, 60 blood samples (one from each patient) and 61 (from 35 patients) NF2-associated tumors were collected. Next-generation sequencing of the blood samples detected \u201cfirst hit\u201d NF2 mutation in 35\/60 donors (58.3%), 82.9% of which (29\/35) bear heterozygous germline mutations, and 17.1% (6\/35) of which are mosaics with variable allelic frequency (VAF). While a number of NF2 patients were found without germline mutation, most (57\/61, 93.4%) NF2-associated tumors were identified with NF2 somatic mutation. We calculated the correlation between the onset latency of mosaic and germline NF2 allele carriers with the mosaicism VAF. The mosaicism VAF is negatively and linearly correlated to clinical symptom onset latency (R2 = 0.3677, P = .00351), suggesting biallelic inactivation probability is a linear function of \u201cfirst hit\u201d prevalence in the body. The second NF2 somatic mutation occurrence time positively correlates with the onset of clinical symptoms (R2 = 0.4151, P = .02633), suggesting tumor growth is linearly proportional to the time after biallelic inactivation.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Our results suggested that biallelic inactivation of NF2 evolved through neutral drift and preexisting first hit NF2 allele determines certain aspects of the clinical symptoms. Genetic diagnosis should be included in the diagnostic criteria and treatment consideration of NF2.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/neuonc\/noab287","type":"journal-article","created":{"date-parts":[[2021,12,15]],"date-time":"2021-12-15T12:46:50Z","timestamp":1639572410000},"page":"903-913","source":"Crossref","is-referenced-by-count":11,"title":["Origins of biallelic inactivation of NF2 in neurofibromatosis type 2"],"prefix":"10.1093","volume":"24","author":[{"given":"Lu","family":"Xue","sequence":"first","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China"},{"name":"Ear Institute, Shanghai Jiao Tong University School of Medicine , Shanghai , China"},{"name":"Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases , Shanghai , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwei","family":"He","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China"},{"name":"Ear Institute, Shanghai Jiao Tong University School of Medicine , Shanghai , China"},{"name":"Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases , Shanghai , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Euler Technology , Beijing , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhigang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China"},{"name":"Ear Institute, Shanghai Jiao Tong University School of Medicine , Shanghai , China"},{"name":"Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases , Shanghai , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongsai","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China"},{"name":"Ear Institute, Shanghai Jiao Tong University School of Medicine , Shanghai , China"},{"name":"Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases , Shanghai , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China"},{"name":"Ear Institute, Shanghai Jiao Tong University School of Medicine , Shanghai , China"},{"name":"Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases , Shanghai , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weidong","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China"},{"name":"Ear Institute, Shanghai Jiao Tong University School of Medicine , Shanghai , China"},{"name":"Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases , Shanghai , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongmei","family":"Liu","sequence":"additional","affiliation":[{"name":"Euler Technology , Beijing , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China"},{"name":"Ear Institute, Shanghai Jiao Tong University School of Medicine , Shanghai , China"},{"name":"Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases , Shanghai , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China"},{"name":"Ear Institute, Shanghai Jiao Tong University School of Medicine , Shanghai , China"},{"name":"Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases , Shanghai , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0977-0920","authenticated-orcid":false,"given":"Zhaoyan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China"},{"name":"Ear Institute, Shanghai Jiao Tong University School of Medicine , Shanghai , China"},{"name":"Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases , Shanghai , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China"},{"name":"Ear Institute, Shanghai Jiao Tong University School of Medicine , Shanghai , China"},{"name":"Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases , Shanghai , China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,12,16]]},"reference":[{"issue":"2","key":"2022060115353332700_CIT0001","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1002\/gcc.2870120206","article-title":"Screening for germ-line mutations in the NF2 gene","volume":"12","author":"M\u00e9rel","year":"1995","journal-title":"Genes Chromosomes Cancer."},{"issue":"3","key":"2022060115353332700_CIT0002","first-page":"529","article-title":"Germ-line mutations in the neurofibromatosis 2 gene: correlations with disease severity and retinal abnormalities","volume":"59","author":"Parry","year":"1996","journal-title":"Am J Hum Genet."},{"issue":"6","key":"2022060115353332700_CIT0003","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1136\/jmg.35.6.450","article-title":"Genotype\/phenotype correlations in type 2 neurofibromatosis (NF2): evidence for more severe disease associated with truncating mutations","volume":"35","author":"Evans","year":"1998","journal-title":"J Med Genet."},{"key":"2022060115353332700_CIT0004","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.ebiom.2018.09.042","article-title":"Synergistic effect of Nutlin-3 combined with MG-132 on schwannoma cells through restoration of merlin and p53 tumour suppressors","volume":"36","author":"Chen","year":"2018","journal-title":"EBioMedicine."},{"issue":"3","key":"2022060115353332700_CIT0005","first-page":"727","article-title":"Somatic mosaicism: a common cause of classic disease in tumor-prone syndromes? Lessons from type 2 neurofibromatosis","volume":"63","author":"Evans","year":"1998","journal-title":"Am J Hum Genet."},{"issue":"2","key":"2022060115353332700_CIT0006","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1136\/jmg.40.2.109","article-title":"Molecular study of frequency of mosaicism in neurofibromatosis 2 patients with bilateral vestibular schwannomas","volume":"40","author":"Kluwe","year":"2003","journal-title":"J Med Genet."},{"issue":"7","key":"2022060115353332700_CIT0007","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1136\/jmg.2006.047753","article-title":"Mosaicism in neurofibromatosis type 2: an update of risk based on uni\/bilaterality of vestibular schwannoma at presentation and sensitive mutation analysis including multiple ligation-dependent probe amplification","volume":"44","author":"Evans","year":"2007","journal-title":"J Med Genet."},{"issue":"1","key":"2022060115353332700_CIT0008","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/s41436-019-0598-7","article-title":"Incidence of mosaicism in 1055 de novo NF2 cases: much higher than previous estimates with high utility of next-generation sequencing","volume":"22","author":"Evans","year":"2020","journal-title":"Genet Med."},{"issue":"7","key":"2022060115353332700_CIT0009","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1136\/jmg.2004.029504","article-title":"The location of constitutional neurofibromatosis 2 (NF2) splice site mutations is associated with the severity of NF2","volume":"42","author":"Baser","year":"2005","journal-title":"J Med Genet."},{"issue":"2","key":"2022060115353332700_CIT0010","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/ng.2855","article-title":"Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas","volume":"46","author":"Piotrowski","year":"2014","journal-title":"Nat Genet."},{"issue":"11","key":"2022060115353332700_CIT0011","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1038\/ng.3688","article-title":"The genomic landscape of schwannoma","volume":"48","author":"Agnihotri","year":"2016","journal-title":"Nat Genet."},{"issue":"4","key":"2022060115353332700_CIT0012","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1073\/pnas.68.4.820","article-title":"Mutation and cancer: statistical study of retinoblastoma","volume":"68","author":"Knudson","year":"1971","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"6089","key":"2022060115353332700_CIT0013","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1038\/323643a0","article-title":"A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma","volume":"323","author":"Friend","year":"1986","journal-title":"Nature."},{"issue":"8","key":"2022060115353332700_CIT0014","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1136\/jmg.2004.027953","article-title":"Age related shift in the mutation spectra of germline and somatic NF2 mutations: hypothetical role of DNA repair mechanisms","volume":"42","author":"Evans","year":"2005","journal-title":"J Med Genet."},{"issue":"47","key":"2022060115353332700_CIT0015","doi-asserted-by":"crossref","first-page":"6216","DOI":"10.1038\/onc.2010.363","article-title":"Rates of loss of heterozygosity and mitotic recombination in NF2 schwannomas, sporadic vestibular schwannomas and schwannomatosis schwannomas","volume":"29","author":"Hadfield","year":"2010","journal-title":"Oncogene."},{"issue":"11","key":"2022060115353332700_CIT0016","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1038\/nrg.2016.104","article-title":"Genetic drift, selection and the evolution of the mutation rate","volume":"17","author":"Lynch","year":"2016","journal-title":"Nat Rev Genet."},{"key":"2022060115353332700_CIT0017","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/s41586-019-1907-7","article-title":"The evolutionary history of 2,658 cancers","volume":"578","author":"Gerstung","year":"2020","journal-title":"Nature."},{"issue":"7","key":"2022060115353332700_CIT0018","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1093\/neuonc\/noy009","article-title":"Targeted next-generation sequencing for differential diagnosis of neurofibromatosis type 2, schwannomatosis, and meningiomatosis","volume":"20","author":"Louvrier","year":"2018","journal-title":"Neuro Oncol."},{"issue":"4","key":"2022060115353332700_CIT0019","doi-asserted-by":"crossref","first-page":"e1004873","DOI":"10.1371\/journal.pcbi.1004873","article-title":"CNVkit: genome-wide copy number detection and visualization from targeted DNA sequencing","volume":"12","author":"Talevich","year":"2016","journal-title":"PLoS Comput Biol."},{"issue":"7809","key":"2022060115353332700_CIT0020","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature."},{"issue":"2","key":"2022060115353332700_CIT0021","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.cell.2018.02.060","article-title":"Comprehensive characterization of cancer driver genes and mutations","volume":"173","author":"Bailey","year":"2018","journal-title":"Cell."},{"issue":"9679","key":"2022060115353332700_CIT0022","doi-asserted-by":"crossref","first-page":"1974","DOI":"10.1016\/S0140-6736(09)60259-2","article-title":"Neurofibromatosis type 2","volume":"373","author":"Asthagiri","year":"2009","journal-title":"Lancet."},{"issue":"9","key":"2022060115353332700_CIT0023","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1097\/GIM.0b013e3181ac9a27","article-title":"Neurofibromatosis 2 [bilateral acoustic neurofibromatosis, central neurofibromatosis, NF2, neurofibromatosis type II]","volume":"11","author":"Evans","year":"2009","journal-title":"Genet Med."},{"issue":"1","key":"2022060115353332700_CIT0024","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1177\/0883073816666736","article-title":"Neurofibromatosis type 2","volume":"32","author":"Ardern-Holmes","year":"2017","journal-title":"J Child Neurol."},{"issue":"6","key":"2022060115353332700_CIT0025","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1136\/jmg.32.6.470","article-title":"Diagnostic issues in a family with late onset type 2 neurofibromatosis","volume":"32","author":"Evans","year":"1995","journal-title":"J Med Genet."},{"issue":"1","key":"2022060115353332700_CIT0026","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1111\/j.1750-3639.1990.tb00636.x","article-title":"Progress toward the isolation and characterization of the genes causing neurofibromatosis","volume":"1","author":"Menon","year":"1990","journal-title":"Brain Pathol."}],"container-title":["Neuro-Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/neuro-oncology\/advance-article-pdf\/doi\/10.1093\/neuonc\/noab287\/42555857\/noab287.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/neuro-oncology\/article-pdf\/24\/6\/903\/43918802\/noab287.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/neuro-oncology\/article-pdf\/24\/6\/903\/43918802\/noab287.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,1]],"date-time":"2022-06-01T15:39:07Z","timestamp":1654097947000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/neuro-oncology\/article\/24\/6\/903\/6464174"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,16]]},"references-count":26,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,12,16]]},"published-print":{"date-parts":[[2022,6,1]]}},"URL":"https:\/\/doi.org\/10.1093\/neuonc\/noab287","relation":{},"ISSN":["1522-8517","1523-5866"],"issn-type":[{"value":"1522-8517","type":"print"},{"value":"1523-5866","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,6,1]]},"published":{"date-parts":[[2021,12,16]]}}}